Unsuspected aspect of immune regulation revealed: Role of 'B cells'

[Ecoclimber]

The Journal of Immunology
A Role for Intrathymic B Cells in the Generation of Natural Regulatory T CellsS. N. Walters, K. E. Webster, S. Daley, S. T. Grey.

From Science Daily
July 1, 2014
Source:
Garvan Institute of Medical Research
Summary:
Until now, the immune cells known as 'B cells' have been thought to specialize only in the production of antibodies. A discovery by immunologists shows they also have a role to play in regulating another important aspect of the immune system. This finding may benefit research into autoimmunity and transplantation.

A discovery by Australian immunologists, uncovering an additional role for antibody-making 'B cells', is considered important enough by the American Association of Immunologists to rank it among the top 10% of articles in the latest issue of The Journal of Immunology, off the press today.

The finding by Senior Research Assistant Stacey Walters and Associate Professor Shane Grey, from Sydney's Garvan Institute of Medical Research, shows that B cells also participate in the development of 'regulatory T cells'.

T cells develop in the thymus gland, a soft triangular organ in the chest cavity. From a 'naïve', or undifferentiated, state they are gradually 'educated' to become helpers, or warriors, or regulators.

Until now, the only non-thymic cells known to educate the regulators were dendritic cells, which travel to the thymus to deliver 'antigen', samples of substances toxic to the body. We now know that B cells can do the same thing.

B cells have been thought to specialise only in the production of antibodies. As newfound educators of T cells as well, B cells become much more interesting and complex characters, potentially useful in helping to prevent organ rejection, or control inflammatory bowel disease, or quell autoimmune conditions.

That is because regulatory T cells control how killer T cells behave -- and can effectively prevent the warriors from attacking 'self' tissue, or tissue perceived as foreign. In the case of organ transplantation, several studies have shown that high levels of regulatory T cells can prevent organ rejection.

"Regulatory T cells are critical in the outcome of an immune response -- so anything that in turn regulates them becomes very interesting to immunologists," said Associate Professor Grey.

"Right now there are clinical trials around the world looking to expand populations of these cells in patients. Researchers are also working on ways to grow regulatory cells in the laboratory -- to infuse into patients as therapy."

"Everyone is interested in finding ways to treat autoimmunity and prevent transplant rejection. Expansion of regulatory T cells should help in both cases."

"Our finding suggests it should be possible to set up systems that harness B cells to expand regulatory cells."

The Garvan lab members worked with mice genetically modified to express high levels of 'BAFF', a substance that increases survival of B cells. The higher number of B cells overall allowed researchers to track the activity of B cells in the thymus.

"It has been known for years that some B cells travel to the thymus, but no-one has understood why," said Stacey Walters.

"Our experiments showed clearly that B cells participated in the creation of regulatory T cells -- the more B cells that were in the thymus, the higher the number of regulatory cells generated. That direct correlation raises interesting possibilities."

"One possibility is using BAFF, a non-toxic substance, to ramp up the B cell count of patients before transplant procedures. It will be very interesting to test whether or not that would prevent rejection."..

 

[Little Bluestem]

bump for those who can understand this.

 

[alex3619]

Interesting. For me this raises an important question: if our B cells are not functioning properly, what happens to our Tregs? Could this explain many of our symptoms? Does Rituximab work not by getting rid of B cells as such, but allowing a whole new population of B cells to come along?

 

[bambi]

It would be nice to have the full paper….http://www.jimmunol.org/content/early/2014/05/27/jimmunol.1302519.abstract

It is well established that Tregs suppress auto reactive B cells. In some autoimmune diseases this mechanism is broken--Tregs are either dysfunctional or decreased in number. Hence the idea is to reintroduce or increase functional Tregs in autoimmune disease. This paper talks about inducing Treg cells via B cells -- but without reading the full paper I am not able to understand what actually is going on. Seems complex...

 

[bambi]

For example, in India researchers claim to have generated T-regs (Regulatory T Cells) in laboratory, which, on being administered to patients, eliminate the need for immunosuppressants after undergoing organ transplantation.

Ahmedabad: In a break through, stem cell researchers here claimed to have found a way out where organ transplantation among the patients could be free of immunosuppressive drugs, which often lead to reduced immunity making their life difficult post transplant.

The researchers claim to have generated T-regs (Regulatory T Cells) in laboratory, which, on being administered to patients, eliminate the need for immunosuppressants after undergoing organ transplantation.

"Researchers infused T-regs in about 27 kidney patients so far after the transplantation. These patients underwent stem cell infusion, followed by kidney transplantation after immune testing and then T-reg infusion," Head of Department of Pathology, Institute of Kidney Diseases and Research Centre-Institute of Transplantation Sciences (IKDRC-ITS), Dr Aruna Vanikar said.

T-regs are a variety of cells that display regulatory function in vitro and in vivo. They play a major role in shutdown of T cell-mediated immunity and are capable of inducing energy towards self and allo-antigens.

"T-regs eliminate requirement for immunasuppressant medications. This is the second major breakthrough that researchers have achieved after generating Mesenchymal Stem Cells (MSC) and hematopoietic stem cells in more than 1,500 renal allograft (transplant) recipients for reducing immunosuppression," she said.

The breakthrough, she said, is expected to create a milestone in all solid organ transplantations and will save patients from associated morbidity and mortality, apart from reducing family`s financial burden.

The generation of T-regs may also help in treatment of diseases like autoimmune disorders, including all kinds of diabetes, hematopoietic disorders like haemophilia and may also help in curing AIDS and cancer, Vanikar claimed.

"Earlier (in 2007), MSC was derived from adipose tissue, a stem cell, which formed into T-regs in the body, reducing chances of rejection of kidney transplantation," Dr Vanikar said, adding that the present research has gone ahead in generating T-regs in laboratories and totally reducing the dependence on immunosuppression medications.

Vanikar said that scientists across the world have been working on "transplantation tolerance" and researchers here were pioneers in achieving the feat.

"The feat has been acknowledged in writing in 40 journals and more than 100 patients, who underwent kidney transplantations, and are living normal life without any dependence on immunosuppressants," Vanikar said.

For this, Shruti Dave, working as a junior research fellow under Vanikar and Prof H L Trivedi at the department of Pathology, IKDRC-ITS, was conferred the most outstanding young researcher in Nephrology award for her work on generation of regulatory-cells from adipose tissue and peripheral blood mononuclear cells.

http://zeenews.india.com/news/healt...ree-of-immunosuppressants-research_20574.html

 

[bambi]

Interesting. For me this raises an important question: if our B cells are not functioning properly, what happens to our Tregs? Could this explain many of our symptoms? Does Rituximab work not by getting rid of B cells as such, but allowing a whole new population of B cells to come along?

It is much more likely that Ritumixab is working because it removes infected B cells.

The increase in Treg cells, plus the other immune markers found to be either activated or decreased in functionality in patient with ME point very clearly to a chronic pathogen. Immune markers combined with other data, such as mothers with one of several children also diagnosed with ME and cluster outbreaks, leaves absolutely no doubt. The question in my mind, and on the mind of Indiana Jones and the virus hunter, is only what kind of pathogen is manipulating the immune system

 

[NK17]

Well said and well thought @bambi. I'd give both my legs to find out who's the orchestra director of the immune dysfunction seen in me (or shall I write ME) and my child!!!


My ME doctor (an immunologist) has several families with different members ill with ME.

In my family I've a history of lymphoma and weak immune system, going back to the early twentieth century.

Why are manly patients like us connecting the dots which only a handful of doctors and scientists are slowly starting to notice and consider!

 

[alex3619]

It is much more likely that Ritumixab is working because it removes infected B cells.

The increase in Treg cells, plus the other immune markers found to be either activated or decreased in functionality in patient with ME point very clearly to a chronic pathogen. Immune markers combined with other data, such as mothers with one of several children also diagnosed with ME and cluster outbreaks, leaves absolutely no doubt. The question in my mind, and on the mind of Indiana Jones and the virus hunter, is only what kind of pathogen is manipulating the immune system

A pathogen is still the dominant hypothesis. However there is evidence this is not the case as well. Its still not determined, and indeed might be different for different subgroups.

 

[bambi]

A pathogen is still the dominant hypothesis. However there is evidence this is not the case as well. Its still not determined, and indeed might be different for different subgroups.

I am not going to argue with Einstein, but which evidence are you talking about ?

 

[bambi]

Why are manly patients like us connecting the dots which only a handful of doctors and scientists are slowly starting to notice and consider!

I think in a large part because the definition of ME is wrong and those responsible for this job have done a really lousy job and have done a really good job at disseminating BS. Than there are those who have hijacked "CFS" for their own interests (good money to be made there) and than, last but not least, we underestimate the stupidity factor.

 

[aimossy]

The Spanish group are looking into the balance of tregs compared to something else I think, but I can't remember the details.
I have a weird question if anybody knows if this may be possible. Could rituximab also decrease or kill off high levels of anaerobic bacteria in the body?

 

[Firestormm]

Pathogen might easily be pathogens... People with our diagnosis can as easily have their symptoms caused by varying or even different 'pathogens' or 'in balances' as they can from the same... Personally I think had it been a single cause responsible we would have unearthed it by now... but then there are causes and there are causes - if a pathogen then how did the pathogen effect a person with ME and not someone else and the same can be said for an in balance say in the microbiome perhaps... even an autoimmune disease... One of the difficulties with 'ME' is the teasing out of subgroups - where to start and where to end and what and how to treat...

 

[adreno]

I'm guessing microbiome imbalances could explain the differences in immune function, and therefore why some people can deal with pathogens and others can't. That's why I believe the Lipkin study is so important.

 

[alex3619]

I am not going to argue with Einstein, but which evidence are you talking about ?

We have been looking for an obvious pathogen cause for a long time, and have not found it. We have evidence that many pathogens can trigger the illness, most of which have three properties in common - they are intracellular pathogens that infect both the gut and B cells. There is a long history of post-polio and post-Q fever, and now we have things like post-SARS and possibly post-Lyme. Of course what "post-" actually is is debatable.

Further we have evidence of ongoing damage to the immune system and metabolism. While a pathogen might be a cause, there are at least three additional possible causes: autoimmunity, autoinflammatory, and mitochondrial dysfunction. We have evidence of all three.

None of this proves its not a pathogen, and my leading contender is enteroviruses, as these have the right lifecycles (not just the lytic lifecycle), incubation period and tissue affinity. Please note that the incubation period that is understood (around 7 days) may only be for the trigger and not the causative agent.

So there are four possible categories of causative agents, not counting risk factors/predispositions like genetics. It looks very much like genetic susceptibility is part of it. So the four possible causes are pathogens, auto-immunity, auto-inflammatory and mitochondrial.

Yet here is the real kicker. It might take more than one to trigger to cause it. These things might work in combination. It might also take more than one pathogen. It might also be that all these things cause it, but in combination all together. Different causes maybe be present in different subgroups.

Other possibilities requiring research include environmental toxins.

The only thing I do not include as causative is any psychogenic hypothesis. They have been proven wrong numerous times, and not once proven right.

We have very close to a diagnostic test in the 2-day CPET. Presuming the science keeps developing the way it has, for mild to moderate (and I think even severe and very severe with modification) we have either a diagnostic test (though we need a much better one) or something that at least proves severe physical disability.

 

[alex3619]

I'm guessing microbiome imbalances could explain the differences in immune function, and therefore why some people can deal with pathogens and others can't. That's why I believe the Lipkin study is so important.

Quite. There are a range of microbiome issues, but the one I am most interested in right now is the possibility of viral infection of the gut bacteria.

 

[alex3619]

I think in a large part because the definition of ME is wrong and those responsible for this job have done a really lousy job and have done a really good job at disseminating BS. Than there are those who have hijacked "CFS" for their own interests (good money to be made there) and than, last but not least, we underestimate the stupidity factor.

"Never underestimate the power of human stupidity." I hope I got the quote right. Robert A. Heinlein.

People are mostly intuitive, not rational. We use reason like we use maths, its a tool that takes work. We get it wrong a lot.

The single biggest factor is human ignorance, not stupidity itself. We are all ignorant. What we do not know far exceeds what we do. People who operate from dogma compound this issue.

 

[adreno]

Quite. There are a range of microbiome issues, but the one I am most interested in right now is the possibility of viral infection of the gut bacteria.

Are you talking about enteroviruses here?

 

[alex3619]

Are you talking about enteroviruses here?

No, bacteriophages. It could possibly be the bacteria infected, not us, but once that happens then crosstalk between the gut bacteria and our immune system will go nuts. Since its not invading us, we also wont have direct immune evidence against it, only indirect evidence like cytokine abnormalities.

 

[Jonathan Edwards]

Interesting. For me this raises an important question: if our B cells are not functioning properly, what happens to our Tregs? Could this explain many of our symptoms? Does Rituximab work not by getting rid of B cells as such, but allowing a whole new population of B cells to come along?

Reasonable questions Alex, but I am not sure just how much we should deduce from this paper. At least as reported in the press release it seems underwhelming. The reality is that we have known that 'B cells do more than produce antibody' including talking to T cells since about 1980! The first monoclonal marker for B cells recognised MHCII, which is what cells use to talk to T cells. Only later was it found on other cells like dendritic cells. B cells have not been seen as important educators in the thymus but does this study help? It seems that in the normal mouse thymus there weren't enough B cells there to study so they had to make transgenic mice with too many B cells, including some in the thymus and they found that these cells talked to T cells there. Not sure what that tells us about even normal mice, let alone humans.

And it seems a bit daft to suggest giving 'non-toxic' BAFF before transplant when we know that acute rejection is mediated at least in part by antibodies and it is quite common to give rituximab (i.e. the opposite) before transplantation and it reduces acute rejection if I remember rightly.

The further irony is that this idea of B cells 'doing other things' has been trendy for a good while. The first time this was 'discovered' (i.e. rediscovered by people who had not read the literature) was about 1994. All the evidence we have on pathogenesis of autoimmunity in humans (animal models are not similar) suggests that B cells are bad news and taking away B cells seems to help. The only thing it may make worse is psoriasis and related disorders that are probably not really autoimmune, but T cell dependent. And there is little or no evidence for Tregs being important in human autoimmunity as far as I know.

In answer to the question about how rituximab helps - it must be because of taking away the B cells because people get better during the period with no B cells and a good proportion get worse again as soon as B cells come back. You never see people getting better when B cells come back.

And in response to another query, I don't think there is any possibility of rituximab removing bacteria. It works directly on B cells and only B cells.

 

[bambi]

We have been looking for an obvious pathogen cause for a long time, and have not found it. We have evidence that many pathogens can trigger the illness, most of which have three properties in common - they are intracellular pathogens that infect both the gut and B cells. There is a long history of post-polio and post-Q fever, and now we have things like post-SARS and possibly post-Lyme. Of course what "post-" actually is is debatable.

Have bee looking for the obvious pathogens, that is the key issue!!! No one looked for the not so obvious one and you would be surprised what can cause exactly the same immune foot print,exercise intolerante, Circadian sleep rythm disorder (non 24 that should interest you), post exertional deteriation, cluster outbreaks and prevalence (vertical transmission) and much more.

Further we have evidence of ongoing damage to the immune system and metabolism. While a pathogen might be a cause, there are at least three additional possible causes: autoimmunity, autoinflammatory, and mitochondrial dysfunction. We have evidence of all three.

Where is your evidence

None of this proves its not a pathogen, and my leading contender is enteroviruses, as these have the right lifecycles (not just the lytic lifecycle), incubation period and tissue affinity. Please note that the incubation period that is understood (around 7 days) may only be for the trigger and not the causative agent.

So there are four possible categories of causative agents, not counting risk factors/predispositions like genetics. It looks very much like genetic susceptibility is part of it. So the four possible causes are pathogens, auto-immunity, auto-inflammatory and mitochondrial.

Yet here is the real kicker. It might take more than one to trigger to cause it. These things might work in combination. It might also take more than one pathogen. It might also be that all these things cause it, but in combination all together. Different causes maybe be present in different subgroups.

Other possibilities requiring research include environmental toxins.

The only thing I do not include as causative is any psychogenic hypothesis. They have been proven wrong numerous times, and not once proven right.

The immune markers found in patients with ME does not indicate autoimmunity - the data is there Alex. We have several good studies now and we have tons of scientific literature to compare and contrast these findings. We know what each marker indicates, what certain immune cell do and which cluster turns up in what kind of disease. These markers and the specific cluster of markers are not some abstract nothing it known about. It might be complex, but in the end if you really study it is is very clear .What can I say more ? You really have to study it to understand it. Sorry, don't want to sound snobby, but it is just like that.

We have very close to a diagnostic test in the 2-day CPET. Presuming the science keeps developing the way it has, for mild to moderate (and I think even severe and very severe with modification) we have either a diagnostic test (though we need a much better one) or something that at least proves severe physical disability.